WO1983000810A1 - Selective carcinostatic agent - Google Patents

Selective carcinostatic agent Download PDF

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Publication number
WO1983000810A1
WO1983000810A1 PCT/JP1982/000356 JP8200356W WO8300810A1 WO 1983000810 A1 WO1983000810 A1 WO 1983000810A1 JP 8200356 W JP8200356 W JP 8200356W WO 8300810 A1 WO8300810 A1 WO 8300810A1
Authority
WO
WIPO (PCT)
Prior art keywords
cells
antibody
substance
carcinostatic
inhibitor
Prior art date
Application number
PCT/JP1982/000356
Other languages
English (en)
French (fr)
Japanese (ja)
Inventor
Limited Suntory
Original Assignee
Nakanishi, Toshihiro
Yoshizumi, Hajime
Imai, Kozo
Yachi, Akira
Ferrone, Soldano
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nakanishi, Toshihiro, Yoshizumi, Hajime, Imai, Kozo, Yachi, Akira, Ferrone, Soldano filed Critical Nakanishi, Toshihiro
Publication of WO1983000810A1 publication Critical patent/WO1983000810A1/ja

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3053—Skin, nerves, brain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6865—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from skin, nerves or brain cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a selective cloner, in particular, a monoclonal antibody (hereinafter abbreviated as "MoAb”) against a human ⁇ antigen produced by a hybridoma and an inhibitor.
  • MoAb monoclonal antibody
  • human cancer cells bound Te chemical 7 manner 4 regarding braking bruises agent having a specific affinity.
  • O PI • An example in which an inhibitor such as downomycin and a Fab 'dimer of antitumor immunoglobulin are covalently bonded (Japanese Patent Application Laid-Open No. 51-144723).
  • the drug of the present invention comprises an active ingredient having an action of suppressing or killing cell growth, and a carrier ingredient carrying the active ingredient and inducing it into cells.
  • the active ingredient has a strong fine-graining action, whether or not it is currently used as an inhibitor, for example endoxan, nitromin , Sanolecolysin, mirane, cyclophosphamide, etc., anorechelating agent, ametbuterin, 8-azaguanine, 5-fluorochloride Nore, cytosine arabinoside, 6—menolecabrin and other antimetabolites; mitomycin (:, actinomycin D, adriaama Lee Thin, da click Roh microstrip Thin, monkey co Ma i Thin any antibiotics; bins bra scan switch down which a Le force port i de; wheat basic Po Li base petit de of (SP 1, etc.
  • the carrier component is a single antibody against the human healing antigen and constitutes a main part of the present invention.
  • These cells were obtained by fusion of appropriate experimental animals sensitized with human pruritic cells, such as XB / c mouse spleen cells and mouse-derived bone marrow sperm cells (myeloma cells). Cloning this with a hybridoma)], selecting fusion cells that produce MoAb, which is capable of binding to human cells and specific binding to human cells. It is obtained by separating and then growing a fused cell capable of producing an antibody capable of binding to the selected specific antigen. The fusion cells (hybrid cells) grown in culture or in the animal body are collected and then the appropriate means are isolated. For the purposes of the invention, this antibody must be as pure as possible.
  • the purified antibody is then chemically conjugated to the desired antitumor agent or cytotoxic agent.
  • This binding is a chemical reaction between the free amino group or carboxy group of the antibody and the amino, carbonyl or aldehyde group of the drug. This is done by the following methods, for example.
  • the conjugate has specificity as an antibody.
  • Fig. 1 is a graph showing the fractionation status of SP-H ⁇ antibody binding reaction product by Sephadex G-200 (elution curve: ⁇ Fig. 2 is SP ⁇ I ⁇ Graphs showing the selective 0 adsorption capacity of the antibody conjugate to Collo 38 cells.
  • Figures 3 and 4 show SP-H'MoAb conjugated Colo 38 cells (melanoma cells). ) And graphs showing the inhibitory effect on Raji cells (normal cells).
  • Figures 5 and 6 show the inhibition of thymidin uptake of SP ⁇ i'MoAb conjugates on Collo38 cells and Raji cells. Effect graph, Fig. 75 shows Adria My. Shin-MoAb conjugate against Colo 38 cells.
  • 8 and 9 are graphs showing the effect of extending the life span of the SP-H'MoAb conjugate according to the present invention on the carrier maxima.
  • the hybridoma (225.28S), which had been pre-cultured in Dunolecco's Modified Eagle Medium (CD-iE3 ⁇ 4 £) or (containing 10% calf serum), was subjected to BALB. Inoculate the abdominal cavity P of the mouse (?, 8 ⁇ : L2 weeks old) with 5 x 10 6 connections. The mice were given 03 weeks of inoculation with Buristein (2,6,10,14-tetramethypententadecane) before inoculation intraperitoneally. Make it easy to grow.
  • OMPI Collect ascites until it is clear.
  • the ascites is centrifuged at 3000 rpm for 10 minutes to remove red blood cells and pristine. Add saturated ammonium sulfate solution to the supernatant while mixing well to a final concentration of 33.3%, and incubate at 4 for at least 1 hour.
  • the resulting precipitate is centrifuged (10000 rpm, 10 min. 4).
  • the collected precipitate was dissolved in a small amount of phosphate buffered saline solution (PBS) without Ca and Mg, and a dialysis tube (Ce1 ophane Tubing-Seamless, United States Union) Carbide) and dialyzed against PBS overnight.
  • PBS phosphate buffered saline solution
  • the MoAb is purified to a single beak by electrophoresis, and the MoAb is also electrophoretically single and can be lyophilized or stored frozen.
  • the culture and purification means for the cultivation and isolation were determined by the method for producing other MoAbs against human malignant melanoma antigens, such as 376.74, 376.96.465.14, 47354.65325 (produced by the hybridoma). Doma and the type of MoAb it produces.) This also applies to: Each antibody specifically binds only to the melanoma antigen, but the binding site differs slightly depending on the type of antibody. This suggests the possibility of catheter therapy using several antibody-drug conjugates at different sites.
  • fractions F-I tubes A9 to A10
  • F--(tubes 12 to 15) are the desired SP-H'MoAb conjugates.
  • fraction F-II tubes ⁇ 26-30
  • Glycerin water (IM) is added to the obtained reaction solution to a final concentration of 0.05 M to decompose excess peroxide soda.
  • 20 mg of the antibody of Example 1 dissolved in a 0.15 M carbonate solution (pH 9.5) is added and reacted at room temperature for 1 hour.
  • Hydrogen sodium hydride was added to the reaction mixture at a ratio of 1 mg / 0.3 mg of the reaction mixture, and the mixture was allowed to stand at 37 ⁇ for 2 hours, followed by gel filtration. Drill Mycin 'MoAb conjugate is obtained.
  • the drug-antibody conjugate obtained in each of the above examples has the property of selectively binding to a target cell.
  • the experimental facts that prove this fact are described below.
  • Colo 38 cells human malignant melanoma cells
  • RMPI1640 medium supplemented with 10% calf serum for Raji Drug: SP-H * MoAb conjugate described in Example 2, dissolved in PBS and applied. Use each medium solution for dilution.
  • Colo 38 and Raji cells are pre-cultured for 3 days, and each cell is washed 5 times with a washing solution having the same composition as the culture solution. Then, each plate is applied to a plastic plate. Spread 5 cells. Add the drug (conjugate) to these plates as the final concentration (0-: LOO) and stir at 4 for 1 hour. Next, the cells were washed 5 times in the same manner, and an appropriate amount of 125 D-labeled butyl A derived from Staph, aureus sp. After washing 5 times in the same manner, the amount of cells attached to the cells is measured using a gamma force counter (manufactured by Beckman C USA). By the way, the ⁇ ⁇ ⁇ binds to the FC part of the union. Therefore, if the conjugate is bound to the cells, protein A will also bind to it, so measure the radioactivity! ? The presence or absence and the degree of the kake are understood.
  • Fig. 2 shows the results of the above experiment.
  • the Col 0 38 with ⁇ shown rather cancer-specific antigen in real ⁇ , Raji not have the antigen are shown in Ten ⁇ .
  • MoAb (225.28S), conjugate I (FI), and conjugate ⁇ (F- ⁇ ) bind to Colo 38 cells according to their concentrations.
  • all of the antibody (225.28S :), conjugate I (F-1) and conjugate ⁇ (F- ⁇ :) were all used.
  • fraction F-— is compatible with Co 10 cells, it is presumed that unreacted SP-H may be present along with the behavior during gel filtration.
  • the unbound drug alone (SP-H) as a control which has an antibody, naturally binds to both Colo and Raji cells.
  • the drug-antibody conjugate according to the present invention clearly has selectivity for antigen cells.
  • the following is an experimental fact that supports this conclusion.
  • the experimental results are shown in Figs. 3 and 4.
  • the conjugates I and ⁇ show cytotoxic effects on Colo 38 cells having melanoma antigen (see FIG. 3), but have a pain antigen and have almost no toxic effects on Raji cells. (See Fig. 4).
  • MoAb C225 28S used as a control did not damage any cells, and the drug alone (SP-II) and fractions, F-II, did not affect any cells. It has a strong disability effect.
  • the substance of the present invention selectively exerts a cytotoxic effect on target cells in a test tube.
  • the target was saturated (human melanoma, Colo38).
  • the substance of the present invention was administered to the mouse, and the efficacy in vivo was examined. The effect was clearly observed.
  • the following is a description of the facts. ⁇ 4!
  • the substance of the present invention may be injected in the form of a tube or muscle injection in a disruptive manner.
  • the conjugate binds to the disease-specific antigen of the target cell, and then is removed locally by phagocytosis and phagocytosis of the cell (pinocytosis)! ? As a result, it is presumed that a killing effect is exerted on the cells. At this time, the conjugate is likely to bind to other normal cells having no adaptive antigen, so that a natural lethal effect appears.
  • the drug-MoAb conjugate according to the present invention shows strong affinity only for specific ⁇ cells having a suitable antigen, kills the pain cells, and Although it has the effect of inhibiting its growth, it has almost no effect on normal cells, and is expected to contribute to the bruising of human beings as a selective therapeutic agent.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Cell Biology (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Neurology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Oncology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Neurosurgery (AREA)
  • Genetics & Genomics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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PCT/JP1982/000356 1981-09-08 1982-09-07 Selective carcinostatic agent WO1983000810A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP56142158A JPS5843926A (ja) 1981-09-08 1981-09-08 選択性制癌剤
JP56/142158810908 1981-09-08

Publications (1)

Publication Number Publication Date
WO1983000810A1 true WO1983000810A1 (en) 1983-03-17

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ID=15308705

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1982/000356 WO1983000810A1 (en) 1981-09-08 1982-09-07 Selective carcinostatic agent

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EP (1) EP0074279B1 (enrdf_load_stackoverflow)
JP (1) JPS5843926A (enrdf_load_stackoverflow)
WO (1) WO1983000810A1 (enrdf_load_stackoverflow)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0226419A3 (en) * 1985-12-06 1988-04-20 Us Commerce Anti-human ovarian cancer immunotoxins and methods of use thereof
EP0226418A3 (en) * 1985-12-06 1988-04-27 Cetus Corporation Anti-human ovarian cancer immunotoxins and methods of use thereof

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58118520A (ja) * 1982-01-09 1983-07-14 Hidematsu Hirai 抗腫瘍性蛋白複合体およびその製造法
US4500637A (en) * 1982-07-19 1985-02-19 The United States Of America As Represented By The Department Of Health And Human Services Prevention of graft versus host disease following bone marrow transplantation
US4520226A (en) * 1982-07-19 1985-05-28 The United States Of America As Represented By The Department Of Health And Human Services Treatment of graft versus host disease using a mixture of T-lymphocyte specific monoclonal antibody: ricin conjugates
GB2131830A (en) * 1982-12-10 1984-06-27 Ludwig Inst Cancer Res Monoclonal antibody for use against breast cancer
FR2546756B1 (fr) * 1983-06-03 1985-11-29 Centre Nat Rech Scient Nouveaux derives immunostimulants, leur preparation et leur application comme medicament
US4753894A (en) * 1984-02-08 1988-06-28 Cetus Corporation Monoclonal anti-human breast cancer antibodies
FR2566271B1 (fr) * 1984-06-20 1986-11-07 Sanofi Sa Nouveaux conjugues cytotoxiques utilisables en therapeutique et procede d'obtention
PT80662B (en) * 1984-06-20 1986-12-09 Sanofi Sa Process to obtain anti-tumoral glycoprotein modified on its glycidic portions
FR2577137B1 (fr) * 1985-02-13 1990-07-13 Sanofi Sa Glycoproteines antitumorales, modifiees sur leurs motifs glucidiques
JPS6136229A (ja) * 1984-07-30 1986-02-20 Kayaku:Kk 選択的制癌物質
CA1339798C (en) * 1985-02-01 1998-04-07 Alan N. Houghton Method for treatment of neuroectodermal malignancies and epithelial carcinomas in humans
FR2577135B1 (fr) * 1985-02-13 1989-12-15 Sanofi Sa Immunotoxines a longue duree d'action comportant un constituant glycopeptidique inactivant les ribosomes modifie sur ses motifs polysaccharidiques
US4744981A (en) * 1985-10-17 1988-05-17 Neorx Corporation Trichothecene antibody conjugates
US5405966A (en) * 1985-10-17 1995-04-11 Theodore; Louis J. Trichothecene conjugates
FR2602683B1 (fr) * 1986-08-12 1990-03-30 Sanofi Sa Immunotoxines a longue duree d'action in vivo comportant une glycoproteine inhibant les ribosomes, modifiee par oxydation des motifs osidiques puis reduction
US4911911A (en) * 1985-12-20 1990-03-27 Sanofi Ribosome-inactivating glycoproteins, modified by oxidation of their osidic units and formation of a schiff's base and in-vivo prolonged action immunotoxins containing such a glycoprotein
US4911912A (en) * 1985-12-20 1990-03-27 Sanofi Ribosome-inactivating glycoproteins, modified by oxidation of their osidic units and reduction, and in vivo prolonged-action immunotoxins containing such a glycoprotein
FR2591895B1 (fr) * 1985-12-20 1988-08-26 Sanofi Sa Immunotoxines a longue duree d'action in vivo comportant la chaine a de ricine modifiee sur ses motifs polysaccharidiques
FR2591894B1 (fr) * 1985-12-20 1988-04-01 Sanofi Sa Immunotoxines a longue duree d'action in vivo comportant la chaine a de ricine modifiee sur ses motifs polysaccharidiques
US4699784A (en) * 1986-02-25 1987-10-13 Center For Molecular Medicine & Immunology Tumoricidal methotrexate-antibody conjugate
US4997913A (en) * 1986-06-30 1991-03-05 Oncogen pH-sensitive immunoconjugates and methods for their use in tumor therapy
FR2601679B1 (fr) * 1986-07-15 1990-05-25 Sanofi Sa Immunotoxines, procede de preparation et compositions pharmaceutiques en contenant
DE3853779T2 (de) * 1987-05-29 1995-09-07 Baylor College Medicine Hiv-1 neutralisierende monoklonale antikörper.
DE3820452A1 (de) * 1988-06-13 1989-12-14 Schering Ag Verfahren zur bildlichen darstellung von tumoren unter verwendung von monoklonalen antikoerpern
CA2021942C (en) * 1989-08-10 2001-04-10 Michel Page Coupling of an anti-tumor to an antibody using glutaraldehyde preactivated anti-tumor agent
US5242813A (en) * 1990-10-12 1993-09-07 The United States Of America As Represented By The Department Of Health And Human Services Mouse monoclonal antibodies specific for normal primate tissue, malignant human cultural cell lines human tumors
DE10328121A1 (de) * 2003-06-23 2005-02-03 Biolife Science Forschungs- und Entwicklungs-GbmH Passive Immuntherapie gegen malignes Melanom
US8318162B2 (en) 2009-07-16 2012-11-27 Xoma Technology Ltd. Antibodies to high molecular weight melanoma associated antigen

Citations (1)

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Publication number Priority date Publication date Assignee Title
JPS5748924A (en) * 1980-07-14 1982-03-20 Univ California Antibody target cell injuring agent

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JPS55136235A (en) * 1979-04-09 1980-10-23 Teijin Ltd Antitumor protein complex and its preparation
JPS5616418A (en) * 1979-07-20 1981-02-17 Teijin Ltd Antitumor protein complex and its preparation
JPS57106626A (en) * 1980-12-22 1982-07-02 Teijin Ltd Cytotoxic protein complex and its preparation
FR2504010B1 (fr) * 1981-04-15 1985-10-25 Sanofi Sa Medicaments anticancereux contenant la chaine a de la ricine associee a un anticorps antimelanome et procede pour leur preparation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5748924A (en) * 1980-07-14 1982-03-20 Univ California Antibody target cell injuring agent

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Medicina, Vol. 19, No. 6, June 1982, "Monoclonal Kotai to Ganchiryo", p. 1022-1023. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0226419A3 (en) * 1985-12-06 1988-04-20 Us Commerce Anti-human ovarian cancer immunotoxins and methods of use thereof
EP0226418A3 (en) * 1985-12-06 1988-04-27 Cetus Corporation Anti-human ovarian cancer immunotoxins and methods of use thereof

Also Published As

Publication number Publication date
EP0074279A3 (en) 1984-03-21
JPH0259128B2 (enrdf_load_stackoverflow) 1990-12-11
EP0074279B1 (en) 1987-08-12
EP0074279A2 (en) 1983-03-16
JPS5843926A (ja) 1983-03-14

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